Exquisite target binding specificity has made antibodies very successful therapeutics and in many cases, safe drugs. Having said that, a subset of these agents exhibits serious, mechanism-based toxicities that limit the use of the drugs and therefore may prevent patients from achieving maximal benefit. At CytomX Therapeutics, our approach is to combine our core competencies of bacterial cell surface display technology and protease substrate engineering to design and build therapeutics, Probodies, that have sufficient efficacy and minimal toxicities for a range of indications. Probodies exploit molecular logic by requiring the presence of a disease-regulated enzyme to become maximally active. Our ongoing research has identified some of the main technical considerations that need to be addressed to optimize these constructs but the preliminary data are quite encouraging. In this research, we plan to design and construct a family of Probodies to the epidermal growth factor receptor (EGFR) using our proprietary peptide discovery technologies. Approved EGFR antagonists are known to produce skin toxicities in the vast majority of patients as well as in non-clinical studies of non-human primates. For these reasons, EGFR was chosen for CytomX's first pre-clinical Probody program. Recognizing that any new protein therapeutic faces many challenges, we have designed this Phase I effort to move the molecules from discovery through cell-based assays to early, outsourced animal testing in an oncology model. In this way, at the close of the project, we will have gained valuable information about the stability and activity of the molecules in vivo as well as a deeper understanding of the discovery process. If successful, we will be poised to embark on a more complete study of the activity and safety of the lead candidate(s) in Phase II and compare these directly to one or more approved agents. PUBLIC HEALTH RELEVANCE: Much can be learned about normal and disease biology from recently approved drugs, their benefits across various pathologies and their side effects. Several targeted therapies exist that show both activity and toxicity due to the distribution of their target in the body. Our R&D efforts plan to take advantage of this knowledge and improve on the targeting of drugs in a wide range of indications, from oncology to rheumatoid arthritis to respiratory and bowel diseases, to improve patient outcomes.